Nadal, who won the past three French Open titles, was bothered by a blister on his right foot and called for the trainer late in the second set.
The blister began bothering Nadal on Sunday, when he won the Barcelona Open.
“Today when I woke up, I said it was impossible to play,” Nadal said. “I spoke to the doctor today and yesterday, and they put special protection on it and cream, but it was still tough.”
Nadal’s last loss on clay came against No. 1 Roger Federer in the Hamburg Masters in May 2007. Before that, Nadal had won a record 81 consecutive matches on the slow, red surface, a streak that began in April 2005.
The second-ranked Nadal had never lost at the Foro Italico, winning the Rome tournament each of the previous three years. The 23rd-ranked Ferrero took the Rome title 2001, two years before he was the French Open champion.
“Juan Carlos is a very tough opponent, but certainly if you’re not 100 percent at a Masters Series event, it is very tough,” Nadal said. “I congratulate Juan Carlos, but today for sure was not my best tennis.”
Nadal, who won the recent Monte Carlo Masters, appeared slightly off his game Wednesday.
Ferrero connected on a cross-court backhand winner to break Nadal and win the first set, then broke again to take a 3-1 lead in the second when Nadal netted a forehand.
“I can’t put the ball long,” Nadal said.
With Ferrero ahead 4-1 in the second set, Nadal called for a trainer and had his foot re-taped. After deciding to play on, he was broken again, then Ferrero served the match out at love.
Ferrero reached the top of the rankings in 2003, on the strength of his title at Roland Garros and runner-up finish at the U.S. Open. Hampered in part by a series of injuries, he has struggled in recent years, finishing outside the top 15 every year since 2003.
The Rome Masters is an important clay-court warm-up tournament for the French Open, which begins May 25.
Earlier Wednesday, third-ranked Novak Djokovic showed no signs of illness when he cruised past Steve Darcis 6-4, 6-0 in his opening match.
In the Monte Carlo Masters, Djokovic pulled out of his semifinal match against Federer after falling behind 6-3, 3-2. Tests afterward revealed he had strep throat.
“I finished with my medication yesterday,” Djokovic said. “So, hopefully, now I’ll get better in the future.”
Against the 49th-ranked Darcis, Djokovic broke at love in the final game of the first set, then rolled through the second.
“I feel good. I’m satisfied with the way I played today. The first match is always tough,” Djokovic said in fluent Italian. “I feel at home in Italy. I like playing here.”
Two seeded players were upset in the second round.
Coming off an appearance in the Barcelona Open final, fifth-seeded David Ferrer lost to Radek Stepanek 4-6, 6-2, 6-1. Spanish clay-court specialist Nicolas Almagro upset seventh-seeded David Nalbandian 6-4, 7-5.
Fourth-seeded Nikolay Davydenko beat Croatian wild card Mario Ancic 6-2, 6-2; No. 8 James Blake held off Andreas Seppi of Italy 7-6 (5), 3-6, 6-1; and No. 12 Fernando Gonzalez — last year’s runner-up — defeated Russian qualifier Evgeny Korolev 6-3, 6-2.
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Slide show
Federer to face nemesis Canas at Rome Masters
Nadal wins 4th straight Barcelona Open
Nadal through to Barcelona Open quarters
Davis Cup city selection gets ugly in Spain
